The present invention relates to histidine derivatives for use as a radiosensitizer in the treatment of cancers including lung carcinomas, breast cancers, prostate cancers, cancers of the cervix and endometrium, neuroblastomas, lymphomas, gliomas, melanomas, squamous cell carcinomas, sarcomas, adenocarcinomas, astrocytomas, head-and-neck tumors, and GI tumors. More particularly, the invention relates to nitrohistidine, alone or in combination with other agents, prepared in slow-release formulations or normal release formulations, for the treatment of the brain tumor glioblastoma multiforme.
Histidine is one of 20 naturally occurring amino acids serving as subunits for proteins. It is often present at the catalytic active site of enzymes. Histidine is one of the nutritionally essential amino acids for mammalian cells, meaning that it cannot be synthesized by mammals, so it must be ingested and then taken up by cells to sustain protein synthesis. Rapidly-growing cells and tissues must be effective at taking up histidine from the environment, and cancer cells, in particular, usually have several very effective amino acid transport systems to aid them in competing for amino acids with other cells and tissues. Previous studies of the active transport of histidine in murine ascites tumor cells (1, 2, 3) indicate that there are two major amino acid transport systems for the uptake of histidine, and most cancer cells necessarily have both systems to permit their continued and rapid growth.
Previous studies have also indicated that nitroimidazoles have some capacity to act as radiosensitizers. Examples include metronidazole (Flagyl), misonidazole, RO-07-0554, RO-11-3696, RO-03-8799 (Pimonidazole), SR-2508 (Etanidazole) and RSU-1069, shown in FIG. 1. These compounds are sometimes referred to as “true radiosensitizers” in that they can apparently substitute for oxygen in “fixing” radiation-induced damage of DNA, making it non-reversible and lethal.
Hypoxic cells are difficult to kill with ionizing radiation compared to normal cells because ionizing radiation requires oxygen to “fix” a lesion transiently induced in DNA by the ionizing radiation in order to kill the cell, and hypoxic cells have little to no oxygen exposure, particularly deep within a tumor. Various attempts to overcome the problem of killing hypoxic cells have been made over the past years. Administration of hyperbaric oxygen or carbogen (a mixture of oxygen and carbon dioxide) has proved problematic, even dangerous, in clinical application, and resulted in mixed results.
A limitation of the nitroimidazole radiosensitizers is that although a number have been found to be effective radiosensitizers in vitro, they have limited practical effectiveness in vivo because they are not concentrated by cancers. Only 5 of 38 clinical trials for the most extensively studied of the nitroimidazoles, misonidazole, suggested any clinical benefit for misonidazole as a radiosensitizer, probably because the compound exhibits poor concentration in tumors.